p-n Heterojunction-based Thermoelectric Generator for Highly Efficient Cancer Thermoelectric Therapy

doi:10.21203/rs.3.rs-319797/v1

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p-n Heterojunction-based Thermoelectric Generator for Highly Efficient Cancer Thermoelectric Therapy

https://doi.org/10.21203/rs.3.rs-319797/v1

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posted 17 Mar, 2021

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Photothermal therapy (PTT) based on the light-heat conversion principle has attracted extensive attention in preclinical research, however, the hyperthermia resulted the treatment-related damage to surrounding tissues prevents further advanced clinical practice. Here, we developed a thermoelectric therapy (TET) based on p-n heterojunction (SrTiO₃/Cu₂Se nanoplates) on the principle of light-heat-electricity-chemical energy conversion, demonstrating great potential for cancer treatment. The principle of TET is based on light-heat-electricity-chemical energy conversion, regarded as an upgraded version of PTT. Upon laser irradiation and subsequently natural cooling-induced the mild temperature gradient (35-45 ^oC), a self-build-in electric field was constructed and thereby facilated electrons and holes separation in bulk SrTiO₃ and Cu₂Se. Importantly, the contact between SrTiO₃(n type) and Cu₂Se(p type) constructed another interficial electric field, which further guided the seperated electrons and holes to transfer to re-locate onto the surfaces of SrTiO₃ and Cu₂Se, respectively. The formation of two electric fields in bulk and interface of SrTiO₃/Cu₂Se nanoplates minimized probability of charges recombination. Of note, high-performance superoxide radicals (·O₂⁻) and hydroxyl radicals (·OH) generation from O₂ and H₂O under catalization by seperated electrons and holes, led to intracellular ROS burst and cancer cells apoptosis without apparent damage to surrounding tissues. As far as it is known, this is the first report on TET based a p-n heterojunction in biomedical field. Construction of bulk and interficial electric fields in heterojunction for improving charges separation and transfer is also expected to provide a robust and universal strategy for diverse applications including energy, environment, and biomedical engineering.

Cancer Biology

Drug Discovery, Design, & Development

Oncology

Photothermal therapy (PTT)

thermoelectric therapy (TET)

Photothermal therapy (PTT), which is based on light-heat conversion, has aroused comprehensive attention and emerged as a potential cancer treatment strategy due to its spatiotemporal addressability, minimal invasiveness, and short treatment time.^1-4 To achieve a high anticancer efficiency, two essential criteria of traditional PTT should be considered, including high photo-thermal conversion performance of the employed photothermal agent (PTA) and long light penetration with minimized tissue scattering and absorption.^5,6 Typically, photothermal conversion efficiency is the critical factor for an eligible PTA, and it is quite necessary for a PTA to increase the temperature of the tumor site above 50 ^oC for achieving a desired therapeutic outcome. Spurred by recent progress in nanotechnology, various PTAs, including gold nanostructure,^7-10 carbon nanomaterials (graphene and its analogs),^11-17 and the recently developed two-dimensional nanomaterials (transition metal dichalcogenides (TMDCs), carbides and nitrides (MXenes), and monoelemental materials (Xenes))^18-24, have currently emerged as efficient materials for PTT-mediated cancer treatment. Additionally, in order to improve light penetration, great endeavors have been devoted to develop the second near infrared ray-based materials (NIR-II) in the spectra range of 1000-1350 nm, which possesses deeper tissue-penetration, reduced light scattering, and higher skin permissible exposure (MPE) than that of NIR-I light.^25-29 Nevertheless, only limited examples of NIR-II PTAs have been reported. Besides, the tissue-penetration of NIR-II light was greatly affected by the strong absorbance band of water overtone, causing potential thermal damage to normal organs and tissues.^30-33 Therefore, despite these great advances achieved to date, most of the existing PTTs are not specifically related to cancer-associated events. That is, although light irradiation could target the tumor site, hyperthermia induced by conventional PTAs or ambient fluid body, would randomly propagate and diffuse to the surrounding normal tissues and organs, and thus results in the treatment-related toxicity and side effects, which are the major obstacle preventing further advanced clinical practice of PTT.

Over the last few decades, thermoelectric (TE) materials, through converting heat to electricity via electron-hole pairs separation under temperature gradient-induced the build-in thermoelectric field, have attracted tremendous attention worldwide in materials science and solid-state physics, due to their wide application in Peltier cooling and waste energy harvesting. ^34-40 Further analysis of the mechanism of TE materials shows the separated electron-hole pairs under build-in thermoelectric field demonstrating great potentials in catalyzing reactive oxygen species (ROS) generation in cushy conditions, similar with the mechanisms of photodynamic therapy and piezocatalytic therapy.^41,42 In addition, compared with PTT-generated hyperthermia, the ROSs have much shorter lifetime and propagation distance in vivo, presumably guaranteeing much less treatment-related side effect or toxicity on surrounding normal tissues and organs. Although TE generators have grown into superstars in the application fields of energy and environment, it is still an infant in biomedical fields. Typically, the thermoelectric figure of merit is the key to evaluate the efficiency of TE materials, ZT = S²sT/k, where S, s, T and k represents Seebeck coefficient, electrical conductivity, temperature, and thermal conductivity, respectively.^43,44 Obviously, the thermoelectric efficiency not only relates to physicochemical properties of TE materials, such as Seebeck coefficient, electrical conductivity, and thermal conductivity, but it also has a linear correlation with the operating temperature, in which higher temperature endows more effective electron-hole pairs separation and higher thermoelectric efficiency, which is also the main obstacle for applications in biomedical fields of TE materials.⁴⁵ Based on our previous studies,^46-50 heterojunction construction, including p-n junction and Z scheme junction, has been demonstrated as an efficient strategy for improving electron-hole pairs separation and enhancing the catalytic efficiency. After contacting of p-type and n-type semiconductors, the interfacial electric field will be constructed, in which the separated electrons and holes in both semiconductors would transfer in the opposite direction and locate in different semiconductors.^51-54 The unfavorable recombination of electron-hole pairs would be retarded, which is the key for conversion efficiency of photocatalysts, electrocatalysts, and TE materials.

Herein, for the first time, we developed a novel thermoelectric therapy (TET) based on light-heat-electricity-chemical energy conversion, by employing SrTiO₃ (n type) and Cu₂Se (p type) to construct a p-n heterojunction, which is capable of dual independently targeted generating ROS under mild temperature gradient (from 35 ^oC to 45^oC). As shown in Figure 1, by employing conventional two-step hydrothermal processes, SrTiO₃/Cu₂Se based p-n heterojunction was constructed. Under 808 nm laser irradiation and natural cooling, the electrons and holes in the bulk of SrTiO₃ and Cu₂Se voluntarily separate and migrate from the bulk to the surface under the driving force of the build-in thermoelectric field on the opposite directions. Additionally, the p-n heterojunction between SrTiO₃ and Cu₂Se constructs an interfacial electric field, and thus redistributes the surface electrons and holes to specific locations for reduction and oxidation reactions, respectively, which further restrains the undesired recombination of electrons-hole pairs in the bulk and on the surface of TE materials. Consequently, a ROS burst under mild temperature gradient and low concentration of TE materials was provided based on a thermoelectric effect. With the goal of complete remission of tumors and without recurrence, our work here presents a novel thermoelectric mechanism based on p-n heterojunction constructed TE generator, with dual independently targeted ROS bursts for efficient cancer therapy and with negligible side effects towards normal tissues. To be noted, we also anticipate the performances of such a p-n heterojunction-constructed TE generator in other settings of biomedical applications beyond cancer treatment.

Preparation and characterization of SrTiO₃/Cu₂Se p-n heterojunction

In the first stage of this work, the SrTiO₃/Cu₂Se p-n heterojunction was synthesized through two steps of hydrothermal process. Detailly, as illustrated in Figure 1, SrTiO₃nanoplates (NPs) (n type TE materials) were papered firstly following Cu₂Se quantum dots (QDs) synthesis and in site coating on the surface of SrTiO₃NPs. After the hydrothermal process and liquid exfoliation, SrTiO₃NPs with a size of 110 nm were analyzed by transmission electron microscopy (TEM) (Figure 2a and Figure S1). Then, Cu₂Se QDs, p type TE materials, were synthesized and coated on the surface of SrTiO₃NPs, forming a novel p-n heterojunction-based TE generator. The successfully coated Cu₂Se QDs was obviously observed in the TEM images of SrTiO₃/Cu₂Se NPs (Figure 2b), in which uniform QDs decoration on the surface of SrTiO₃NPs was exhibited. The size of the prepared SrTiO₃/Cu₂Se NPs was appropriately increased to about 132 nm (Figure S2). Additionally, the high-resolution transmission electron microscopy (HRTEM) images with clear interference fringe and d-spacing of 0.27 nm and 0.33 nm, corresponding to the plane of SrTiO₃NPs (Figure 2c) and Cu₂Se QDs (Figure 2d), provided a direct evidence for the successful fabrication of the heterojunction structure. Besides, atomic force microscope (AFM) was also applied to characterize the morphology of the fabricated SrTiO₃/Cu₂Se NPs. As shown in Figure 2d and 2e, a rough surface was clearly observed, which was likely attributed to the coating of Cu₂Se QDs. Calculation from the 2D and 3D AFM images of SrTiO₃/Cu₂Se NPs, the NPs displayed a planar size of about 132 nm and thickness of 50 nm. Given that almost all thermoelectric materials have a good piezoelectric property,^55-57 we determined the piezoelectric properties of SrTiO₃/Cu₂Se NPs by a piezoresponse force microscope (PFM), using dual alternating current resonance tracking (DART) modes with the aim to expel the displacement contribution from electrostatic interaction and topographical crosstalk in mapping the local electromechanical properties. Figure 2e-2h exhibited the topographic, vertical piezoresponse amplitude, and phase images of the SrTiO₃/Cu₂Se NPs, respectively. The SrTiO₃/Cu₂Se NPs can be clearly detected in the topographic image with clear contrast in the amplitude and phase images. Figure 2g exhibited the phase map of SrTiO₃/Cu₂Se NPs, which well matches the morphology map in Figure 2e. Next, a surface potential of 30 mV of SrTiO₃/Cu₂Se NPs was observed in the piezoelectric potential map of SrTiO₃/Cu₂Se NPs (Figure 2h) obtained by PFM in the darkness, which demonstrates its piezoelectric property and further testifies its thermoelectric property. To further confirm the successful fabrication and the composition of SrTiO₃NPs, Cu₂Se QDs and SrTiO₃/Cu₂Se NPs, X-ray photoelectron spectroscopy (XPS) and X-ray diffractometry (XRD) were performed. In the XPS analysis (Figure 3a), the specific peaks of Sr, Ti, O, and Cu, Se, were exhibited in their XPS spectra, respectively. Moreover, all these characteristic peaks were observed in the XPS spectrum of SrTiO₃/Cu₂Se NPs. In the XRD spectrum (Figure 3b), two respective structures corresponding with SrTiO₃and Cu₂Se were observed. All above observations confirmed the successful fabrication of the heterojunction structure and their potential thermoelectric property of SrTiO₃/Cu₂Se NPs.

The biomedical applications of nanomedicine largely depend on their physiological dispersibility and stability. It was observed that the surfaces of SrTiO₃/Cu₂Se NPs were slightly negatively charged after the hydrothermal process, (Figure S3), which allowed surface modification by using amphipathic DSPE-PEG through hydrophobic interaction. The zeta potential of SrTiO₃/Cu₂Se NPs increased to -30 mV, demonstrating a successful PEG modification and thus ensuring their physiological dispensability and stability. Around 25% (w/w) of DSPE-PEG was loaded on the surface of the SrTiO₃/Cu₂Se NPs as measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). PEGylation of SrTiO₃/Cu₂Se NPs showed improved dispersion in cell culture medium, phosphate buffer saline (PBS) and water in contrast with the bare SrTiO₃/Cu₂Se NPs due to lack of aggregation (Figure S4). In addition, the Fourier transform infrared (FT-IR) absorption bands of the PEGylated SrTiO₃/Cu₂Se NPs at ~1250 cm⁻¹ and ~2900 cm⁻¹ are corresponded to the C=O stretching vibration and -CH vibrations in the DSPE-PEG segment (Figures S5). Finally, Sr (red), Ti (green), and O (blue) appeared in the energy dispersive spectrometry (EDS) mapping of SrTiO₃ NPs, and after Cu₂Se QDs and PEG coating, Cu (purple), Se (olive), C (yellow), and N (white) showed again in the EDS mapping of PEGylated SrTiO₃/Cu₂Se NPs (Figure 2i), further confirmed successful surface coating by DSPE-PEG.

Next, the thermoelectric performance of our prepared SrTiO₃/Cu₂Se NPs were examined. The ZT of SrTiO₃ NPs and Cu₂Se QDs were tested and calculated, respectively. Figure 3c shows the material-dependent s as a function of temperature. It is apparently that s increases monotonically with increasing the temperature for these two samples and roughly follows a co-efficient of T^-1.5, suggesting that acoustic phonons dominate the carrier scattering. Figure 3d shows the variations of S with the temperature. The positive signal of S indicates the p-type nature for Cu₂Se QDs, and the negative signal of S indicates the n-type nature for SrTiO₃ NPs. S increases gently upon increasing the temperature. Figure 3e presents the plots of S²s as a function of temperature, from which relatively high S²s of SrTiO₃ NPs and Cu₂Se QDs were obtained. Figure 3f is the plots of κ as a function of temperature, in which the relatively low κ of SrTiO₃ NPs and Cu₂Se QDs were also obtained. Due to the obtained high S²s as well as low κ, significantly enhanced ZT values are expected. Figure 3f is the ZT plots as a function of temperature, in which a peak ZT of 0.11 and 0.17 at 333 K is achieved in the fabricated SrTiO₃ NPs and Cu₂Se QDs. Figure 3h shows the S at room temperature as a function of the natural logarithm of s of SrTiO₃ NPs and Cu₂Se QDs. This linear relationship between the S and the natural logarithm s indicates more fluctuating carrier concentration and less varying carrier mobility. All above observations confirmed the good thermoelectric properties of SrTiO₃/Cu₂Se NPs.

SrTiO₃/Cu₂Se NPs mediated reactive oxygen species (ROS) generation

Followingly, the light-heat-electricity-chemical energy conversion of SrTiO₃ NPs, Cu₂Se QDs, and SrTiO₃/Cu₂Se NPs were measured and analyzed. Figure 4a and 4b show the light-heat conversion of SrTiO₃/Cu₂Se NPs, in which the temperature increased from 35 ^oC to 45 ^oC under 2.5 min 808 nm laser irradiation and cooled down to 35 ^oC following 9 min natural cooling process. As shown in Figure 4h, according to thermoelectric effect, under temperature gradient (35^oC - 45 ^oC) induced by 808 nm laser irradiation and natural cooling, a build-in electric field was constructed on the opposite surfaces of SrTiO₃ NPs or Cu₂Se QDs. Therefore, the built-in electric field can facilitate separation of charges (electrons and holes) in bulk, and promote their transfer to the catalyst surface, making them effective tools for catalyzing reduction and oxidization of O₂ and H₂O to generate superoxide anion (·O₂⁻) and hydroxyl radical (·OH), respectively. ·O₂⁻ generation through the reduction of electrons was measured with dihydrorhodamine 123 (DHR 123) probe. As shown in Figures 4c and 4e, obvious fluorescence increase was detected following the temperature gradient (35^oC - 45 ^oC) using SrTiO₃ NPs and Cu₂Se QDs separately, which indicated that SrTiO₃ NPs and Cu₂Se QDs are suitable nanomedicines for thermoelectric therapy. Of note, a much stronger fluorescence increase was observed when SrTiO₃/Cu₂Se NPs were applied as thermoelectric catalysts for catalyzing ·O₂⁻ generation from O₂. As exhibited in Figure 4h, after SrTiO₃ NPs (n type) contacting with Cu₂Se QDs (p type), an interfacial electric field was then constructed on their interface, in which the separated electrons and holes induced by thermoelectric effect further transferred and re-located on the surface of different catalysts following interfacial electric field. Thereby, the recombination of electrons and holes was restricted, leading to extending lifetime of separated electrons and holes for further redox reactions. The p-n heterojunction enhanced thermoelectric effect of SrTiO₃/Cu₂Se NPs was further assessed in terms of hydroxyl radical (·OH) production using methylene blue (MB) as the specific probe of ·OH. Consistent with the above results, the SrTiO₃/Cu₂Se NPs exhibited the strongest ·OH generation, which further confirmed their p-n heterojunction enhanced thermoelectric effects (Figure 4d and 4f). By employing 5,5-dimethyl-1-pyrroline N-oxide as the spin trapping agent, electron spin resonance (ESR) was applyed to detect the gnerated ROS directly. As shown in Figure 4g, ·O₂⁻ and ·OH synchronously generated from SrTiO₃/Cu₂Se NPs through thermoelectric effects from O₂ and H₂O were detected, which further confirms the high ability of ROS generation of SrTiO₃/Cu₂Se NPs.

In vitro antitumor evaluation mediated by SrTiO₃/Cu₂Se NPs

The biocompatibility of the prepared TE agents was next tested using MCF 7 and Hela cancerous cells. As shown in Figure 5a and S7, similar with the traditional photothermal agent (graphene, G), the TE agents showed negligible cytotoxicity in the absence of excitation, and more than 80% of the cells were viable even when exposed to 100 mg/mL of the respective TE agents. Stimulation with 808 nm laser led to the temperature increasing from 35 ^oC to 45 ^oC, and thus increased the cytotoxic effects of all TE agents (Figure 5b and S8). However, under the uniform 808 nm laser irradiation and temperature increase, the cells treated with G still remain a relatively high viability.To this end, we speculated that the cytotoxic effects of TE agents are probably attributed to the thermoelectric effect inducing ROS generation, rather than photothermal effect inducing heat. With increasing cycles of this temperature gradient (35^oC - 45 ^oC), an enhanced cell cytotoxic effects of TE agents were observed, meanwhile, the cytotoxic effects of G remain negligiblely improved. This observation further demonstrated the thermoelectric effect of TE agents inducing ROS generation was the main cause for their cytotoxicity. Moreover, the cells treated with SrTiO₃/Cu₂Se NPs exhibited the highest cytotoxicity, confirming the p-n heterojunction enhanced thermoelectric effect. Additionaly, the intracellular ROS levels under different treatments were analyzed by using fluorescent probe. Indeedly, the intracellular ROS levels were signficantly higher in the SrTiO₃ NPs and Cu₂Se QDs treated groups, compared to those treated with G, and the highest ROS concentration was detected in cells exposed to the SrTiO₃/Cu₂Se NPs coupled with 808 nm laser irradiation and a natural cooling process (Figures 5d and 5e). As previously reported,⁵⁸ DNA damage caused by ROS is one of the main causes for ROS-induced cell toxicity. Thus, the levels of DNA damage in MCF 7 cells after different treatments were further analyzed using γ-H2AX as a marker for DNA double-strand breaks. As shown in Figure 5f, MCF 7 cells treated with G with DT (35^oC - 45 ^oC) did not show any obvious DNA damage compared with the control group. However, MCF 7 cells treated with SrTiO₃ NPs or Cu₂Se QDs coupling with the same DT, showed apparently detectable levels of DNA damage, further supporting the TE effect of SrTiO₃ NPs and Cu₂Se QDs. Treatment with SrTiO₃/Cu₂Se NPs and DT produced considerably high levels of irreparable DNA damage in the cancer cells. All these results thus suggest that the developed therapeutic strategy based on SrTiO₃/Cu₂Se NPs and DT with an enhanced TE effect can specifically kill cancer cells. Moreover, the efficient apoptosis of SrTiO₃/Cu₂Se NPs via TE effect was further detected through co-staining cells with propidium iodide (PI, dead cells, red fluorescence) and calcein AM (live cells, green fluorescence) after different treatments. The LSCM images of co-stained cancer cells, as shown in Figure 5g, also confirmed the antitumor effect of TET in vitro.

In vivo antitumor evaluation mediated by SrTiO₃/Cu₂Se NPs

The anti-cancer potential of TET was next evaluated in vivo using MCF 7 tumor-bearing mice. The mice were each injected intravenously with Cy7-labeled NPs at the dosage of 5 mg/kg, and the fluorescence intensity of Cy7 in the blood was measured at different time intervals. As shown in Figure 6b, the Cy7-loaded NPs remained signficantly longer in circulation compared to free Cy7, which was suggestive of greater tumor accumulation of NPs. Additionally, the tumor accumulation of NPs was also confirmed by fluorescence imaging of major organs after 24 h i.v. injection (Figure 6c). To more precisely characterize the biodistribution of NPs in vivo, an ICP was employed to test the concentration of NPs in the major organs and tumors over 24 hours, which also showed a great tumor accumulation of the prepared NPs. The MCF 7 tumor-bearing mice were randomly divided into the following groups and treated accordingly: 1) saline control, 2) SrTiO₃/Cu₂Se NPs, 3) SrTiO₃ NPs + DT, 4) Cu₂Se QDs + DT, 5) SrTiO₃/Cu₂Se NPs + DT, 6) G + DT, and 7) PTT (G, >55^oC). The DT means temperature gradient (35^oC - 45 ^oC) for 3 cycles inducing by 808 nm laser irradiation and natural cooling after 24 h post injection (Figure 6a and 6e). The tumor volume was measured every 2 days, and as shown in the growth curves in Figure 6f and 6g, the untreated and non-DT controls did not show any significant inhibition of tumor growth. The combination of TE agents (SrTiO₃ NPs or Cu₂Se QDs) and DT achieved an obvious inhibitory effect, which is attributed to the generation of ROS by the thermoelectric effect. Due to the p-n heterojunction enhanced thermoelectric effect, SrTiO₃/Cu₂Se NPs with DT markedly inhibited tumor growth, in which SrTiO₃/Cu₂Se NPs almost completely ablated the tumors under the same conditions. In contrast, the G NSs with the same DT treatment exhibited only a slight inhibition of tumor growth compared with the control group, which indicated the temeperature of 45^oC can not able to induce cancer cells death. Only the hyperthermia (>55^oC) induced by G NSs-mediated PTT could provide a similar anti-tumor effect as that of TET (45^oC) (Figure 6h). However, as shown in Figure 6g, because the hyperthermia (>55^oC) randomly propagated and diffused to the surrounding tissues, an obvious PTT-related toxicity and side effects on normal tissues was observed, in which the skin and muscle at the 808 nm laser irradiation site were scorched. By contrast, there was negligible damage to the skin at the irradiated sites of TET (45^oC) (Figure 6f). These findings are consistent with the thermoelectric effect and heterojunction structure of SrTiO₃/Cu₂Se NPs that induces an intracellular ROS burst. The representative images of mice from the different treatments are shown in Figure 6f and 6g. Moreover, the mice treated with SrTiO₃/Cu₂Se NPs + DT showed the longest lifetime without any tumor recurrence (Figure 6l). No signficant changes were observed in the body weight of the mice during the experimental period (Figure S10), indicating negligible adverse effects of this therapy in vivo.

The intracellular ROS burst effect was further validated by using DCFH fluorescence probe. As shown in Figure 6i and S11, the different treatments led to consistent ROS accumulation in the tumors, and the strongest green fluorescence was detected in the SrTiO₃/Cu₂Se NPs + DT group, further indicating a drastic ROS burst in tumor cells. Given that ROS induce apoptosis through DNA damage,⁵⁸ we next analyzed the tumors for signs of DNA double strand breaks, oxidative stress and apoptosis. SrTiO₃/Cu₂Se NPs alone induced negligible γ-H2AX foci and very few apoptotic cells, whereas both DNA damage and apoptosis were considerably higher under SrTiO₃ NPs or Cu₂Se QDs with DT. Coupling SrTiO₃/Cu₂Se NPs and DT led to a marked increase in γ-H2AX foci and apoptosis in the tumors (Figure 6j and 6k). Furthermore, the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidized DNA, were consistent with that of γ-H2AX (Figure S12). Taken together, the p-n TE agents heterojunction can efficiently trigger a ROS burst in cancer cells and induce apoptosis under a mild condition.

Biocompatibility evaluation of SrTiO₃/Cu₂Se NPs

The biocompatibility of TET was evaluated via hematological, histological and immunological indices. As shown in Figure 7a-7c, no obvious difference in ROS levels, DNA damage, apoptosis, and tissue damage were observed in normal tissues after treatment with SrTiO₃/Cu₂Se NPs + DT compared with those treated with PBS, indicating a favorable biocompatibility of the SrTiO₃/Cu₂Se NPs and TET in normal tissues. Moreover, the serum levels of IFN-γ, IL-6, TNF-α and IL-12+P40 were similar in the control and treated mice 12 and 24h post i.v. injection of SrTiO₃/Cu₂Se NPs (10 mg/kg) (Figure 7d). In addition, routine blood examination on days 1, 7 and 14 post-injection did not show any significant differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT), white blood cells (WBC), blood urea nitrogen (BUN), alkaline phosphatase (ALP), red blood cells (RBC), platelet (PLT), Hemoglobin (HGB), mean corpuscular volume (MCV), creatinine (Cr), lymphocyte (LYM), hematocrit (HCT), and neutrophil (NEU) between the control and treated groups (Figure 7e). Taken together, SrTiO₃/Cu₂Se NPs and TET are biocompatible in vivo.

Comparation of side effects between PTT and TET

As demonstrated above, PTT with hyperthermia (>55^oC) could easily damage the skin at irradiated site. To further confirm the superiority of TET, we finally compared the treatment-related toxicity and side effects on normal tissues and organs through simulating the PTT and TET at some major organs and tissues. As exhibited in Figure 8, exposure to the TET (45^oC) conditions, negligible toxicity or side effect are observed in their H&E staining images of heart, liver, spleen, lung, kidney, muscle, and skin, compared with these without any treatment. However, obvious and serious damages were revealed in these important organs and tissues after exposing to the PTT (55^oC) conditions. For example, congestion, enlargement of intercellular space, tissue defect, etc, were presented in these major organs. Additionally, evident swelling and critical damage were also observed in muscle and skin under treated with PTT (55^oC). All above phenomena further confirmed the in vivo safety of TET and demonstrated competitive advantages over PTT.

In summary, a novel TET based on p-n heterojunction TE generator was successfully developed and demonstrated outstanding anticancer potency with negligible side-effects. The SrTiO₃/Cu₂Se NPs based p-n heterojunction was prepared by simple two-step hydrothermal processes, exhibiting an excellent thermoelectric effect under mild temperature gradient from 35 ^oC to 45^oC. The formation of build-in electric field induced by thermoelectric effect under temperature gradient allowed directional separation of electrons and holes in the bulk of SrTiO₃ NPs and Cu₂Se QDs. Furthermore, the interfacial electric field induced by contacting of SrTiO₃ NPs (n type) and Cu₂Se QDs (p type) further guided the distribution and re-location of the excited electrons and holes onto the surface of SrTiO₃ NPs and Cu₂Se QDs, respectively. The synergy between build-in and interfacial electric fields facilitated the electrons and holes separation and transfer both in the bulk and the interface, minimizing the undesired charge recombination. Under 808 nm laser irradiation and natural cooling induced temeprature gradient (35-45^oC), the engineered SrTiO₃/Cu₂Se NPs serve as an intelligent TE generator with dually independent ROS (·O₂⁻ and ·OH) generation through catalyzing the oxidation and reduction of O₂ and H₂O in tumor microenvironment. With an effective ROS burst mediated apoptosis of cancer cells both in vitro and in vivo, the p-n heterojunction TE generator based TET has been demonstrated to be a novel and potential clinic cancer treatment. This work is also expected to provide a smart strategy for the design of other p-n heterojunction TE generator with efficient charges separation and will inspire future studies in expanding their in-depth application, especially in other biomedical applications, such as diabetic ulcer treatment and wound infection resistance under temperature difference between the body and outside environment.

Materials

Ti(OBu)₄, Sr(NO₃)₂, NaOH, (CH₂OH)₂, Se, CuI, H₂N(CH₂)NH₂, 9,10-anthracenedipropanoic acid (ABDA), [Ru(dpp)₃]Cl₂ (RDPP), H₂O₂ (30%), N-methyl-pyrrolidone (NMP), methylene blue (MB), 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB), and dihydrorhodamine 123 (DHR123) were supplied by Sigma-Aldrich.DSPE-PEG-Cy7 (MW: 5k) and DSPE-PEG (MW: 5k) were purchased from Nanocs Inc. PBS (pH 7.4 and 5.5), DMEM medium, RPMI medium, trypsin-EDTA, and fetal bovine serum (FBS) were purchased from Gibco Life Technologies.

Synthesis of SrTiO₃/Cu₂Se NPs

The SrTiO₃/Cu₂Se NPs based p-n heterojunction was prepared by simple two-step hydrothermal processes. First, SrTiO₃NPs were synthesized by a hydrothermal method using Teflon lined stainless steel autoclave containing the mixture of (CH₂OH)₂, NaOH, Sr(NO₃)₂, and Ti(OBu)₄. After the steel autoclave was heated at 180 ^oC for 24 h, the obtained powder was under probe sonication–assisted liquid exfoliation in NMP for 5 h. Then, the solution was centrifuged at 3000 rpm for 5 min to obtain SrTiO₃NPs. For Cu₂Se QDs coating, CuI and Se powders were placed in a Teflon lined stainless steel autoclave containing 30 mL ethylenediamine and prepared SrTiO₃NPs. After the steel autoclave was heated at 90 °C for 4 h, the precipitate was centrifuged at 3000 rpm and washed with distilled water for 3 times. Then, the prepared products were dried in vacuum at 50 °C for 4 h. The final black products (SrTiO₃/Cu₂Se NPs) were collected.

For surface modification, DSPE-PEG was dissolved into the SrTiO₃/Cu₂Se NPs solution and stirred for 12 hours after 30 min of sonication. Then the solution was centrifuged for 30 min at 5000 rpm with Amicon pipes (MWCO 100kDa; Millipore) and the precipitates were washed 3 times to remove the residual DSPE-PEG. The same process was used for fluorescent modification of SrTiO₃/Cu₂Se NPs using DSPE-PEG-Cy7 in a dark environment.

Characterization

The zeta potential and corresponding size of SrTiO₃/Cu₂Se NPs were detected through Dynamic Light Scattering. The morphology of SrTiO₃/Cu₂Se NPs was observed with transmission electron microscopy (TEM, JEM-2100UHR, JEOL, Japan) and atomic force microscopy (AFM, FASTSCANBIO, Germany). Piezoresponse force microscopic (PFM) measurements were characterized by an AFM (NTEGRA, NT-MDT, Russian) equipped with a ferroelectric test system. The SrTiO₃/Cu₂Se NPs chemical constituents were detected by energy-dispersive X-ray spectroscope (EDS) (Inca X-MAX, Oxford, UK), X-ray photoelectron spectroscopy (XPS, ESCALAB 250Xi, Japan), and fourier transform infrared spectrophotometry (FTIR, Nexus 470, Nicolet, Madison, WI, USA). The SrTiO₃/Cu₂Se NPs chemical structures were characterized by employing X-ray powder diffraction (XRD, Bruker D8 multipurpose). As for thermoelectric properties, a laser flash method (LFA 457, NETZSCH) was utilized to measure thermal diffusivity (D), while a ZEM-3, ULVAC was used for the analysis of s and S.

OH production in vitro

The mixture of SrTiO₃ NPs, Cu₂Se QDs or SrTiO₃/Cu₂Se NPs and MB were prepared in PBS (pH 7.4) and stirred for 1 hour in a dark environment at the corresponding final concentration of 0.050 mg/mL TE agents and 0.05 mg/mL MB, respectively. Then the mixture was irradiated with 808 nm laser (1 W/cm²) for 2.5 min and cooled naturally for 10 min. The diminished MB was determined by recording the absorption of the supernatant via UV-vis spectroscopy.

O₂⁻ production in vitro

The mixture of SrTiO₃ NPs, Cu₂Se QDs or SrTiO₃/Cu₂Se NPs (0.05 mg/mL) and DHR123 (1 μL,1 mM) were formed in PBS (pH 7.4) and stirred for 1 hour in a dark environment. Then the mixed solution was irradiated via 808 nm laser (1 W/cm²) for 2.5 min and natural cooling for 10 min. The changing fluorescence of DHR123 was recorded by fluorescence spectrophotometer.

Electron Paramagnetic Resonance (EPR) for ·OH and ·O₂⁻ in vitro

For further detection of the ·OH and ·O₂⁻ formation, SrTiO₃/Cu₂Se NPs (0.05 mg/mL) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) (0.1 mM) were fully mixed (solution for testing ·OH: DI water, solution for testing ·O₂⁻: methanol). The respective signals were analyzed by Electron Paramagnetic Resonance (EPR).

Cytotoxicity of TE agents

MCF 7 and Hela cells were plated and cultured in 96-well microplates (37 °C, 5% CO₂) for 24 hours. Then the SrTiO₃ NPs, Cu₂Se QDs or SrTiO₃/Cu₂Se NPs at different concentrations (ranging from 0.025 mg/mL to 0.1 mg/mL) were mixed into the culture medium. Following 24h co-incubation, MTT assay (Life Technologies) was conducted to determine cell viabilities according to the manufacturer’s instructions.

Production of ROS in cells

After 24 hours of culture (37 °C, 5% CO₂) in dishes, MCF 7 cells were incubated with the SrTiO₃ NPs, Cu₂Se QDs and SrTiO₃/Cu₂Se NPs (final concentration of 0.05 mg/mL) respectively for another 24 hours. Next, the DCFH-DA solution (final concentration of 0.2 μM) was put into the above medium and incubated for 0.5 hours. Following removing the culture medium and washing with PBS, the cells were illuminated for 2.5 min employing an 808 nm light with power 1 W/cm² and cooled naturally for 10 min. The green fluorescence induced by ROS was detected by CLSM.

In vitro TET

MCF 7 and Hela cell lines were plated in 96-well plates and cultured for 24 hours (37 °C, 5% CO₂). Then the SrTiO₃ NPs, Cu₂Se QDs or SrTiO₃/Cu₂Se NPs at different concentrations (ranging from 0.025 mg/mL to 0.1 mg/mL) were mixed into the culture medium and incubated for another 24 hours. Following culture medium removing and PBS washing, the cells were illuminated for 2.5 min employing an 808 nm light with power 1 W/cm² and cooled naturally for 10 min. After 24-hour culture, the cells were washed with PBS for several times. MTT assay was applied to detect cell viability.

Pharmacokinetic study

To conduct in vivo pharmacokinetic study, 200 μL of Cy7 functionalized SrTiO₃/Cu₂Se NPs (5 mg/kg) were i.v. injected in C57BL/6 mice. After different intervals, a microplate reader was utilized to test fluorescent intensity of Cy7 through the collected 20 μL blood.

In vivo imaging and biodistribution study

For the sale of fluorescence imaging and biodistribution study in vivo, 200 μL of Cy7 functionalized SrTiO₃/Cu₂Se NPs (5 mg/kg) were i.v. injected into mice bearing MCF 7 tumors. The Maestro2 In-Vivo Imaging System was employed to detect the fluorescent intensity of tumor and major organs 24 hours post-injection.

In vivo TET

After the tumors had reached to ~100 mm³, mice were randomly allocated into 6 groups, 5 mice in each group. 1) saline control, 2) SrTiO₃/Cu₂Se NPs, 3) SrTiO₃ NPs + DT, 4) Cu₂Se QDs + DT, 5) SrTiO₃/Cu₂Se NPs + DT, 6) G + DT, and 7) PTT (G, >55^oC). The DT means temperature gradient (35-45^oC) for 3 cycles inducing by 808 nm laser irradiation and natural cooling after 24 h post injection The volume of tumors was monitored every two days lasting 14 days.

In vivo toxicity

C57BL/6 mice were i.v. injected with SrTiO₃/Cu₂Se NPs (10 mg/kg) in order for toxicity analysis in vivo. Major organs were collected and subjected to eosin (H&E) and hematoxylin staining 30 days postinjection. Then the immune response was analyzed through the i.v. injection of SrTiO₃/Cu₂Se NPs (10 mg/kg) into C57BL/6 mice. At 12 hours and 24 hours post-injection, ELISA was used to measure the concentrations of interleukin6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). At day1, 7, and 14 after intravenous injection, urea nitrogen (BUN), creatinine (Cr), albumin (ALB), total protein (TP), aspartate alanine aminotransferase (ALT), and aminotransferase (AST) were detected in a whole blood panel.

Statistical analysis

Data statistics and statistical significance were calculated by using Graph Pad Prism 8.0 and Origin 9.0. And NPs biodistribution and tumor volume were analyzed via employing Microsoft Excel 2016.

Data availability

The authors declare that all data supporting the findings of this study are available within the article and the Supplementary Information. Other data are available from the corresponding authors upon reasonable request.

Competing interests

The authors declare no competing interests.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81801826 and 32071322); Science, Technology & Innovation Commission of Shenzhen Municipality (No. JCYJ20180307153300735)

Author contributions

X.J. designed the project. X.J. and C.P. synthesized and characterized the materials. C.P., M. O., and Y. W. performed all the in vitro and in vivo experiments. X.J., Q. X., and L. M. discussed the results and interpreted the data. X.J., Q. X., and L. M. co-wrote the paper, and all authors commented on and approved it.

Statement of ethics approval

All animals received humane care, and the Animal Ethics Committee of Sun Yat-sen University approved all the animal experiments. All experiments were carried out according to the recommendations of the Institutional Animal Care and Use Committee of Sun Yat-sen University (Guangzhou, China).

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p-n Heterojunction-based Thermoelectric Generator for Highly Efficient Cancer Thermoelectric Therapy

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